1. Technical Field
This invention relates to novel chemical compounds useful as cholinergic drugs, processes for preparing and pharmaceutical compositions containing such compounds, and methods for using them in the treatment of disease.
The invention further relates to novel compounds which act on cholinergic receptors of the central and peripheral nervous system. More particularly, it relates to certain compounds which are selective agonists and antagonists for subtypes of muscarinic cholinergic receptors, to processes for the preparation of such compounds, and to pharmaceutical compositions comprising them which can be used therapeutically for the treatment of diseases and disorders associated with such receptors in humans and animals.
2. Description of Background Art
Muscarinic pharmacological behavior was first distinguished from its nicotinic cholinergic counterpart by Dale in J. Parmacol. Exper. Ther., 6, 147-90 (1914). As used herein, the term "muscarinic cholinergic receptors" denotes that class of cholinergic receptors which are activated by acetylcholine and also by the alkaloid muscarine. Compounds such as muscarine which activate muscarinic receptors, in addition to binding strongly to them, are termed muscarinic "agonists" or muscarinic "cholinomimetics". Certain chemical compounds such as atropine bind to muscarinic cholinergic receptors but do not lead to a pharmacological response and, in fact, block the effects of acetylcholine and muscarinic agonists; they are termed muscarinic cholinergic "antagonists" or "cholinolytics". Finally, some compounds have less pharmacological potency than so-called "full" muscarinic agonists (i.e., those with unit intrinsic activity); they are termed "partial agonists". Muscarinic receptors are located on the smooth muscle and glands which they innervate. They are also found in ganglia and between neuronal synapses, and are generally located post-synaptically and/or pre-synaptically. Muscarinic cholinergic receptors can be visualized using radioactively-labeled muscarinic agonists or antagonists.
Heretofore, there has been much discussion in the neurosciences literature on muscarinic receptor subtypes analogous to alpha and beta adrenergic receptor subtypes and histamine H1 and H2 subtypes. Classification of muscarinic receptors into two subtypes, M.sub.1 and M.sub.2, has been proposed by Goyal and Rattan based upon the differentiating effects of partially selective agonists NcN-A343 and bethanechol on the one hand, and the partially-selective antagonists pirenzepine and DAMP on the other. See Goyal et al., Gastroenterology, 74, 598-618 (1978). According to animal assay, M.sub.1 -activating behavior is associated with relaxation of the lower esophageal sphincter of an anaesthetized opossum; M.sub.2 -activating behavior is associated with contraction of the lower esophageal sphincter. This unique model has served well in the identification and localization of receptor subtypes of neurohormonal substances. See Goyal et al., supra, and Rattan et al., J. Pharmacol. Exper. Ther.m 224, 391-7 (1983).
Accordingly, it is an object of the present invention to provide chemical compounds which are highly selective agonists and antagonists for muscarinic receptor subtypes, and which are useful for clinical applications in the treatment of memory and cognitive disorders including such senile dementias as Alzheimer's disease, problems of gastrointestinal motility and secretion, cardiovascular problems and other disease conditions arising from and/or related to muscarinic cholinergic function or disfunction. The invention is also intended to provide chemical compounds which enhance and promote mental functions such as memory and coordination among healthy people. Yet another object is to provide methods for preparing the aforesaid compounds, pharmaceutical compositions containing them and procedures for administering the compounds to patients afflicted with the aforementioned disorders.